3-hydroxymethyl-4-phenyltetrahydro-pyridines and their esters



nited tates B HYDROXYIVIETHYL4-PHENYL'IETRAHYDRG- PYRIDINES AND THEIRESTERS No Drawing. Application October 7, 1954, Serial No. 461,024

6 Claims. (Cl. 260-2955) This invention concerns3-hydroxytnethyl-4-phenyltetrahydropyridines having an N-alkyl orN-benzyl group and esters of these alcohols. This invention also dealswith processes for the preparation of these compounds.

While simple hydroxymethyltetrahydropyridines have been reported in theliterature; they have lacked the 4-phenyl group and other structuralfeatures which would support their utility in the pharmaceutical fieldor to yield functional derivatives which are thus useful.

We have found that 1-substituted-4-phenyl-l,2,3,6- tetrahydropyridinescan be reacted with formaldehyde in the presence of sulfuric acid togive1-substituted-3-hydroxymethyl-4-phenyl-1,2,3,6-tetrahydropyridines. Thereaction is usually effected between 75 and about 110 C., or highertemperatures if pressure is used. The reaction product is separatedafter neutralization of acid in the reaction mixture. The product canoften be distilled and sometimes can be crystallized for purposes ofpurification.

Reaction of these alcohols with carboxylic acids or their anhydridesyields esters. Useful pharmacologically active esters can be formed byconventional esterification methods from such monocarboxylic acids asacetic, propionic, and butyric, or from such a dicarboxylic acid assuccinic. These esters have analgetic and antispasmodic properties.

As an alternate method for preparing these esters, we have found that a1-substitutd-4-phenyl-1,2,3,6-tetrahydropyridine can be reactedwithformaldehyde in the presence of sulfuric acid in a monocarboxylicacid as solvent. In this way, the ester iidirectly isolated.

As a primary reactant there-is used a l-substituted-4-phenyltetrahydropyridine of the structure phenyl including those fromnaphthyl compounds may be used.

A convenient way to make these l-substituted-4-plienyltetrahydropyridines comprises starting with an ut-methylstyrene,reacting itwithlformaldehyd'e and a vprimary, non-'aromatic amine,RNH2,"in the presence of av hydrohalide as catalyst, thus forming a6-methyl-6- phenyLi-substituted tetrahydro-l,3-oxazine, and convertingthis compound by heating it .between 75 and 150 G. inthe presenceofexcess of aqueous hydrochloric or sulfuric acid or other non-oxidizingacid stronger than Kid converted to4-phenyl-1-substituted-1,2,3,6-tetrahydropyridine, and separating thisproduct.

The first reaction, that of olefinic compounds includinga-methylstyrene, formaldehyde, and primary amines,

.is described by Hartough et al. in U. S. 2,647,117. This reaction canyield as a main product a tetrahydro-l,3- oxazine. Here it is necessaryto use an a-methyl compound and to have the phenyl group on the a-carbonatom. The phenyl group can carry one or more inert substituents, such asmethyl, ethyl, isopropyl, or butyl, or chloro. Thetetrahydro-l,'3-ox'azines may be separated in their basic form.

Typical conversions of such oxazines to the 4-phenyltetrahydropyridineswhich are here reacted with formaldehyde are shown in the followingtypical preparation s.

- PREPARATION A PREPARATION 2 A mixture of 75 parts of water, 15 partsof concentrated sulfuric acid, and 78 parts of 3-n-hexyl-6-methyl-6-phenyltetrahydro-1,3-oxazine (n 1.5268) was stirred on a steam bathfor six hours, allowed to stand overnight, poured into 1000 parts ofwater and made alkaline with caustic. The liberated basic material wasextracted with toluene, dried over anhydrous potassium carbonate, anddistilled to give 20 parts of l-n-hexyl-4-phenyltetra- '--hydropyridine,distilling at 137-l42 C./0.75 mm. and

stirred at 90-95 C. for another" hour.

having a refractive index, n of 1.5347.

PREPARATION 3 To 73 parts of 3,6-dimethyl-6 phenyltetrahydro-l,3-oxazine was slowly added 100'parts of concentrated hy drochloric acid.The mixture .wasstirred at 95 C. for three hours, allowed to standovernight, and then After being diluted with 300 parts. of water,thesolution was made basic with sodium hydroxide and the liberated basicmaterial was extracted with two 90 part portions of henzene, dried overanhydrous potassium carbonate, stripped,

and distilled to give 57 parts of l-methyl4-phenyltetrahydropyridine,distilling at 8095 C./0.75 mm. Hg. Neutral equivalent: found-172,calculated-173.

PREPARATION 4 A mixture of 60 parts of water, 120 parts of concentratedsulfuric acid, and 74 parts of 3benzyl-6methyl-6- ptolyltetrahydro-1,3-oxazine was stirred and heated at -100 C. for sixhours.

hours and poured into 500 parts of water. The resulting mixture was madealkaline with aqueous sodium hydroxide solution. The basic product wastaken up with toluene, The toluene solution was driedover anhydrous.

potassium carbonate and distilled. At l68,l75 ,C./0.7

Patented May 29, 1956 It was left standing for 16 Eatample- 1 A mixtureof 165 parts of water, v117 parts ofconcentrated sulfuric acid, and 99parts of 91% paraformaldehyde was heated andstir'red'until. a. clearsolutionwas obtained and was then cooled-to C; There was .addedslowly132' parts of 1-methyl 4 phenyltetrahydropyridine and the mixture was'stirredona steam bath for .7 hours and allowed to stand overnight. Itwas poured into 1000 parts of water andmade basicwith excess sodiumhydroxide. The organic base separated and was extracted with benzene.The benzeneextract wasdried over anhydrous potassium carbonate and upondistillation yielded 90 parts of 1-methyl 3-hydroxymethyl 4phenyltetrahydropyridine, distilling at 130-140 C./ 1 mm. This 'productcrystallized upon standing and was recrystallized'from' abenzene-heptanemixtureto give 'a whitesolid, melting at 98400 C. Amixed melting-pointwith thematerial made by a different method: of synthesis-showedno de*pression. This product contained by analysis 76i58 'of carbon, 8.46% ofhydrogen, .and 6.82% ofinitrogen Calculated values'are 76.8%, 8.43%, and6;89%rrespec-' tively. This compound has the structure Example 2 Amixture of 99. parts of 91% paraformaldehyde', 165. parts of water, and117 parts ofconce'ntratedfsulfuric acid wasstirred and heated until -aclearsolutionwas ob tained. It was then cooled to 50 C. and 146 parts of3,6-dimethyl-6-phenyltetrahydro-1,S-oxazine were added slowly withstirring and cooling. The mixture was stirred and heated under reflux.for 24 hours,cooled andpoured intol000'parts of .water. The aqueoussolutioniwas extracted with toluene and 'was then madeb'asic with excesssodium hydroxide .solution; The liberated Yiorganicbase was taken up.with toluene, driedfoverianhydrouspotas= sium carbonate, anddistilled'togive '67 partsofi l meth'yl 3 hydroxymethyL t-phenyltetiahydropyridine;distilling at 125445 C'./0.7 mm. This' materialcrystall'i'z'edupomstanding and wasrrecrystalliie'd iffom-benzenvheptane =to give-a--whit'e-'solid melting at 98 l0o CT A-mixedmelta ing point with theproduct of Example 1 showed no depression:

Example 3 A mixture of 26 parts of water, 19 parts of concentratedsulfuric acid, and" 161 parts of paraformaldehyde was heated and stirredto a clear solution and then cooled to SO CY There-was added 25 parts of1-n-buty1-4- phenyltetrahy'dropyri'dine and themixture was stirred at95400 C. for'5 hours, allowed to stand overnight, poured into"300partsiofwater, andmade basic with caustic. The liberated basic'materialwas extracted with toluene, dried over anhydrous potassium carbonate,and distilled ito give -15 parts .of: 1-n-butyl-3-hydroxymethyl-4-phenyltetrahydropyridine,.distilling at 145-160 C./0.7 mm. This producthad a neutral equivalent of 245 (theory 245) and" a refractive index, nof 1.5412. This compound has the structure (EaHt It contains 'byanalysis 5.82%-of nitrogen (theory 5 .71%).

Example 4 A mixture of '33' parts of water, 22 parts of concentratedsulfuric acid, and 19 parts of paraformaldehyde was stirred and warmedto a clearsolution'andthen cooled to 50 C. There was added 35.5 parts ofl-benzyl- 4-p-tolyltetrahydropyridine and the mixture was stirred at-100 C. for three hours, cooled, poured into 500 parts of water, andmade basic with caustic soda solution. The liberated material wasextracted with toluene,

dried over potassium'carbonate, and distilled to give 34 parts of1abenzyl-3-hydroxymethyl 4-p-tolyltetrahydropyridine, distilling at200-210 C./1 mm. This crystallized .on standing and was recrystallizedfrom. heptaneto givea'white solidmelting at 102104 C. This compound hasthe structure onion N IC 0115 It contains by analysis 82.17% of carbon,8.00% of hydrogen, and 4.86% of nitrogen; Theoretical values are 81.89%,7.90%, and 4.78%wrespectively.

In the same way other N-substituted 4-phenyl-1,2,3.6-tetrahydropyridines are reacted with formaldehyde to give the3-hydroxymethyl derivatives. These compounds are useful" as corrosioninhibitors, having a favorable balance of properties from the presenceof thesolubilizing'hy droxy" group and'the'hydrophobic phenyl group. The

alcohols. are'also useful as chemical intermediates, reacting, forexample, with" ethylene'oxide to give-polyethoxyethanolswhichlhavesurface active properties, particularly when the phenyl grouphas one 'or more hydrocarbonsubstituents. Other reactions 'arediscusse'dbelow."

cedures: arebest shown by the following: illustrative:-

examples-3 Conditions 1 for carrying out such reactions are Example To amixture of 100 parts of 20% caustic and 8.0 parts of1-methyl-3-hydroxymethyE-4-phenyltetrahydropyridine was added 18.2 partsof bcnzoyl chloride. The mixture was well shaken, cooled, and extractedwith ether. The ether extract wa dried over potassium carbonate,filtered, and stripped to give parts of a solid residue which wasrecrystallized from heptane and from a heptanetoluene mixture to-1-rnethyl-3-benzoxymethyl-4-phenyltetrahydropyridine. This compoundmelted at 80-83 C. and had a neutral equivalent of 303 (theory 307).Analysis of this compound gave the following data: carbon, 77.66%;hydrogen, 6.87%; and nitrogen, 4.34%. Corresponding theoretical valuesare 78.14%, 6.89%, and 4.56% respectively.

Example 6 A mixture of 58 parts of 1-methyl-3-hydroxymethyl-4-phenyltetrahydropyridine, 250 parts of propionic anhydride, and 1 partof concentrated sulfuric acid was stirred and heated at l00110 C. forthree hours, stripped to about 200 parts, poured into 1000 parts ofwater, extracted with two 100 part portions of toluene, and made basicwith aqueous caustic soda solution. The liberated base was cxtrated withtoluene, dried over anhydrous potassium carbonate, and distilled to give36 parts of 1-methyl-3-propionoxymethyl 4 phenyltetrahydropyridine,distilling at 125140 C./ 0.85 mm. It had a neutral equivalent of 253(theory 259). Redistillation gave a center cut, distilling at 127-132C./0.62 mm. which had a refractive index, n of 1.5368 and a neutralequivalent of 255. This product contained by analysis 74.10% of carbon,8.16% of hydrogen, and 5.40% of nitrogen. Theoretical values are 73.38%,8.11%, and 5.60% respectively.

Example 7 A mixture of 72 parts of 1-methyl-3-hydroxymethyl-4-phenyltetrahydropyridine, 300 parts of acetic anhydride, and 1 part ofconcentrated sulfuric acid was stirred at 100-110" C. for four hours,allowed to stand overnight, stripped to about 150 parts, poured into 500parts of water, and made basic with aqueous caustic soda solution. Theliberated base was extracted with toluene, dried over anhydrouspotassium carbonate, and distilled to give 54 parts of1-methyl-3-acetoxymethyl-4-phenyltetrahydropyridine, distilling at118-126 C./0.65 mm. This was redistilled to a center cut, distilling at117-120 C./0.65 mm. It had a refractive index, n of 1.5425 and a neutralequivalent of 236 (theory 245). It contained by analysis 72.99% ofcarbon, 8.10% of hydrogen, and 5.80% of nitrogen. Correspondingtheoretical values are 73.44%, 7.81%, and 5.71% respectively. Thiscompound has the structure phenyl CHzO OCCHa Example 8 A mixture of 300parts of glacial acetic acid, parts of acetic anhydride, 99 parts ofparaformaldehyle, and 117 parts of concentrated sulfuric acid wasstirred and warmed until a homogeneous solution resulted. There was thenslowly added 132 parts of 1-methyl-4-phenyltetrahydropyridine and themixture was stirred and heated at 95100 C. for six hours. Excess aceticacid was removed under reduced pressure and the mixture was then pouredonto 1000 parts of ice and made alkaline with caustic soda and potassiumcarbonate. The material which separated was extracted with toluene,dried over anhydrous potassium carbonate, and distilled to give 40 6parts of 1-methyl-3-acetoxymethyl-4-phenyltetrahydropyridine, distillingat 116-l21 C./0.75 mm. Hg and having a refractive index, n of 1.543.

In the same way any other of the l-substituted-4-phenyltetrahydropyridines herein describedvmay be con verted to theanalogous 3-acetoxymethyl compound. Propionic acid may likewise be usedas solvent and reactant to give corresponding propionoxymethylderivatives.

While the esters and alcohols'of this invention exhibit importantpharmacological action, they are of even more interest as intermediatesfor forming other compounds of pharmacological value. For example, thedouble bond can be hydrated to yield interesting glycols, which in turncan be converted into 1,3-dioxanes by reaction with aldehydes. Thesecombine the pharmacological activities of the 1,3-dioxane group and the4-phenylpiperidine group.

By reaction of the 3 hydroxymethyl 4 phenyltetrahydropyridines andthionyl chloride there are obtained the 3-chloromethyl derivatives,which contain this reactive group and from which many kinds ofderivatives are readily prepared. For example, hydration and reductivedehydrohalogenation yield the important alcohol Similarly, reaction withsodium malonic ester followed by hydrolysis and decarboxylation yieldsthe six-membered lactone Hydration of the 1 substituted 3hydroxymethyl-4- phenyl-1,2,3,6-tetrahydropyridines can be accomplishedas shown in the following typical reaction.

A mixture of 11 parts of 1-methyl-3-hydroxymethyl-4-phenyltetrahydropyridine and 200 parts of glacial acetic acid issaturated with anhydrous hydrogen bromide at 10-20" C. over the courseof 2 hours. The mixture is allowed to stand at room temperatureovernight and is stripped to a dry solid under reduced pressure at amaximum temperature of 45 C. The residue is dissolved in 200 parts ofwater and is heated on a steam bath at C. for 2 hours, cooled, and madebasic with excess sodium hydroxide. The material which separates fromsolution is extracted with a mixture of toluene and ether, dried overanyhydrous potassium carbonate, filtered, and the filtrate is strippedof solvent under reduced pressure. A

white solid is obtained which is recrystallized from toluene-heptanemixture to give a white solid melting at 146-148 C. In a typicalpreparation the product thus obtained had a neutral equivalent of 220.The theory .for 1;.-, methyl 3 -:hydroxymethy1 4- phenyl 4hydroxypiperidine isg221.

The compounds :which. are of direct interest in this invention havethestructure phenyl 'CH'iOR 1 where R is a member of the class.consisting of bcnzyl and alkyl groups, R is a member of the classconsisting of hydrogen, acyl groups of two to four carbon atoms and thebenzoyl group, and :A1' is a member of the class con- 30 sisting of theCeHsand .CHzCeI-I4-, groups.

2. Compounds. of .therstructure lloHs where R is an alkyl group of notover four carbon atoms.

I 8 3. A compound of the structure 4. A compound of the structure CoHs'CHaOH 5. A compound. of the formula ClluHu CHaOE .(JHaCsHs 6. Acompound of the-formula CHzOOCOH:

References Cited in the file of this patent Karrer: Chem. Abst., vol.43, col. 2582 (1949).

1. COMPOUNDS OF THE STRUCTURE